maytansine and Small-Cell-Lung-Carcinoma

The identification of epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangements and the development of targeted therapy for patients with these molecular alterations has been a tremendous advance in the treatment of advanced stage or metastatic non-small cell lung cancer (NSCLC). However, the majority of patients with advanced stage NSCLC will not have one of these molecular alterations and will receive chemotherapy as their primary therapy. Chemotherapy remains a critical component of therapy for resected and locally advanced NSCLC, as well as for patients with limited-stage and extensive stage small cell lung cancer (SCLC). A significant unmet need exists to develop novel chemotherapy agents and to improve the efficacy and toxicity of currently available agents. Several novel formulations of currently available chemotherapy agents are in development for NSCLC and SCLC. Antibody conjugates are therapeutic agents that employ a tumor-specific monoclonal antibody conjugated to a cytotoxic or radionuclide agent. After the monoclonal antibody binds to the tumor antigen, these agents are internalized, and the link between the antibody and the therapeutic agent is dissolved and the cytotoxic agent is release intracellularly. This enhanced delivery of chemotherapy to malignant tissues has the potential to improve efficacy and reduce toxicity. Antibody conjugates to therapeutic agents are currently available for other malignancies and are in development for NSCLC and SCLC.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Hodgkin Disease; Humans; Liposomes; Lung Neoplasms; Lymphoma, Non-Hodgkin; Maytansine; Small Cell Lung Carcinoma

Topics: Animals; Antibodies, Monoclonal, Humanized; Carboplatin; Cell Line, Tumor; Cell Proliferation; Etoposide; Female; Humans; Immunoconjugates; Lung Neoplasms; Maytansine; Mice; Proto-Oncogene Proteins c-kit; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-2; Small Cell Lung Carcinoma; Trastuzumab; Tubulin Modulators; Xenograft Model Antitumor Assays

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate with no improvement to treatment in decades, and new therapies are desperately needed. PEN-221 is a miniaturized peptide-drug conjugate (∼2 kDa) designed to target SCLC via a Somatostatin Receptor 2 (SSTR2)-targeting ligand and to overcome the high proliferation rate characteristic of this disease by using the potent cytotoxic payload, DM1. SSTR2 is an ideal target for a drug conjugate, as it is overexpressed in SCLC with limited normal tissue expression.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Gene Expression Regulation, Neoplastic; Humans; Immunoconjugates; Lung Neoplasms; Maytansine; Mice; Miniaturization; Receptors, Somatostatin; Small Cell Lung Carcinoma; Up-Regulation; Xenograft Model Antitumor Assays

Overcoming chemoresistance is essential for achieving better prognoses in SCLC. Previously, we reported that HER2 is upregulated when HER2-positive SCLC cells acquire chemoresistance. HER2-upregulated cisplatin- or etoposide-resistant SCLC cells were sensitive to trastuzumab-mediated ADCC. However, irinotecan-resistant SCLC cells, such as SBC-3/SN-38, were refractory to trastuzumab despite high HER2 expression. To address this issue, we examined the antitumor efficacy of trastuzumab emtansine (T-DM1) on trastuzumab-resistant HER2-positive SCLC. Treatment with T-DM1 significantly suppressed the growth of SBC-3/SN-38 xenografts in mice compared with trastuzumab (P < 0.05). Histological analysis of xenografts was performed to evaluate the therapeutic effect on apoptosis, proliferation and tumor vasculature. T-DM1 monotherapy induced apoptosis in SBC-3/SN-38 xenografts to a greater extent than trastuzumab monotherapy with the apoptotic index of 3.71 ± 1.56% vs. 0.60 ± 0.32% (P < 0.05), and also inhibited the proliferation of tumor cells compared with trastuzumab with the proliferative index of 74.30 ± 5.54% vs. 80.12 ± 4.81% (P < 0.05). On the other hand, no significant difference in micro vessel density was observed between the treatment groups. In vivo imaging using fluorescence-labeled T-DM1 showed that intravenously administered T-DM1 was rapidly delivered to xenografts and continued to accumulate for several days in a HER2-selective fashion. From these findings, delivery of the cytotoxic agent DM1 into cells via HER2-mediated internalization is expected to exert antitumor effect in such ADCC-lacking SCLC cells. Collectively, T-DM1 will be a promising option for overcoming trastuzumab-resistance in HER2-upregulated SCLC.

Topics: Ado-Trastuzumab Emtansine; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Injections, Intravenous; Lung Neoplasms; Maytansine; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms, Experimental; Receptor, ErbB-2; Small Cell Lung Carcinoma; Structure-Activity Relationship; Trastuzumab; Tumor Cells, Cultured; Xenograft Model Antitumor Assays